Histamine is one of the most potent mediators of immediate hypersensitivity reactions. While the effects of histamine on smooth muscle cell contraction, vascular permeability and gastric acid secretion are well known, its effects on the immune system are only now beginning to become unveiled.
A few years ago, a novel histamine receptor, which was named H4, was cloned by several research groups working independently (Oda T et al, J Biol Chem 2000, 275: 36781-6; Nguyen T of al, Mol Pharmacol 2001, 59: 427-33). As the other members of its family, it is a G-protein coupled receptor (GPCR) containing 7 transmembrane segments. However, the H4 receptor has low homology with the three other histamine receptors (Oda T of al); it is remarkable that it shares only a 35% homology with the H3 receptor. While the expression of the H3 receptor is restricted to cells of the central nervous system, the expression of the H4 receptor has been mainly observed in cells of the haematopoietic lineage, in particular eosinophils, mast cells, basophils, dendritic cells and T-cells (Oda T et al). The fact that the H4 receptor is highly distributed in cells of the immune system suggests the involvement of this receptor in immuno-inflammatory responses. Moreover, this hypothesis is reinforced by the fact that its gene expression can be regulated by inflammatory stimuli such as interferon, TNFα and IL-6. Nevertheless, the H4 receptor is also expressed in other types of cells such as human synovial cells obtained from patients suffering from rheumatoid arthritis (Wojtecka-Lukasik E et al, Ann Rheum Dis 2006, 65 (Suppl 11): 129; Ikawa Y et al, Bio/Pharm Bull 2005, 28: 2016-8) and osteoarthritis (Grzybowska-Kowalczyk A of al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, P-11), and in the human intestinal tract (Sander L E et al, Gut 2006, 55: 498-504). An increase in the expression of the H4 receptor has also been reported in nasal polyp tissue in comparison to nasal mucosa of healthy people (Jókúti A et al, Cell Biol Int 2007, 31: 1367-70).
Recent studies with specific ligands of the H4 receptor have helped to delimit the pharmacological properties of this receptor. These studies have evidenced that several histamine-induced responses in eosinophils such as chemotaxis, conformational change and CD11b and CD54 up-regulation are specifically mediated by the H4 receptor (Ling P et al, Br J Pharmacol 2004, 142:161-71; Buckland K F et al, Br J Pharmacol 2003, 140:1117-27). In dendritic cells, the H4 receptor has been shown to affect maturation, cytokine production and migration of these cells (Jelinek I et al, 1st Joint Meeting of European National Societies of Immunology, Paris, France, 2006, PA-1255). Moreover, the role of the H4 receptor in mast cells has been studied. Although H4 receptor activation does not induce mast cell degranulation, histamine and other proinflammatory mediators are released; moreover, the H4 receptor has been shown to mediate chemotaxis and calcium mobilization of mast cells (Hofstra C L et al, J Pharmacol Exp Ther 2003, 305: 1212-21). With regard to T-lymphocytes; it has been shown that H4 receptor activation induces T-cell migration and preferentially attracts a T-lymphocyte population with suppressor/regulatory phenotype and function (Morgan R K et al, American Thoracic Society Conference, San Diego, USA, 2006, P-536), as well as regulating the activation of CD4+ T cells (Dunford P J of al, J Immunol 2006, 176: 7062-70). As for the intestine, the distribution of the H4 receptor suggests that it may have a role in the control of peristalsis and gastric acid secretion (Morini G of al, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, O-10).
The various functions of the H4 receptor observed in eosinophils, mast cells and T-cells suggest that this receptor can play an Important role in the immuno-inflammatory response (see e.g. Zampeli E and Tiligada E, Br J Pharmacol, 2009, 157, 24-33). In fact, H4 receptor antagonists have shown in vivo activity in murine models of peritonitis (Thurmond R L at al, J Pharmacol Exp Ther 2004, 309: 404-13), pleurisy (Takeshita K et al., J Pharmacol Exp Ther 2003, 307: 1072-8) and scratching (Bell J K et al, Br J Pharmacol 2004, 142:374-80). In addition, H4 receptor antagonists have demonstrated in vivo activity in experimental models of allergic asthma (Dunford P J et al, 2006), inflammatory bowel disease (Varga C et al, Eur J Pharmacol 2005, 522:130-8), pruritus (Dunford P J at al, J Allergy Clin Immunol 2007, 119: 176-83), atopic dermatitis (Cowden J M at al, J Allergy Clin Immunol 2007; 119 (1): S239 (Abs 935), American Academy of Allergy, Asthma and Immunology 2007 AAAAI Annual Meeting, San Diego, USA), ocular inflammation (Zampeli E at at, European Histamine Research Society XXXVI Annual Meeting, Florence, Italy, 2007, O-36), edema and hyperalgesia (Coruzzi G of al, Eur J Pharmacol 2007, 563: 240-4), and neuropathic pain (Cowart M D et at, J Med. Chem. 2008; 51 (20): 6547-57). Histamine H4 receptor antagonists may also be useful in cancer (see e.g. Cianchi F et al, Clinical Cancer Research, 2005, 11(19), 6807-6815).
It is therefore expected that H4 receptor antagonists can be useful among others for the treatment or prevention of allergic, immunological and inflammatory diseases, pain and cancer.
Accordingly, it would be desirable to provide novel compounds having H4 receptor antagonist activity and which are good drug candidates. In particular, preferred compounds should bind potently to the histamine H4 receptor whilst showing little affinity for other receptors and ion channels. In addition to binding to H4 receptors, compounds should further exhibit good pharmacological activity in in vivo disease models. Moreover, compounds should reach the target tissue or organ when administered via the chosen route of administration and possess favourable pharmacokinetic properties. In addition, they should be non-toxic and demonstrate few side-effects.